The overall objective of the work proposed in this grant is to find novel drugs that help to prevent metastasis. In Phase I, newly available natural product extracts will be tested to find compounds that specifically target genes that are critical for the Epithelial to Mesenchymal Transition (EMT) in several different tumor cell models. Many lines of evidence suggest that tumor cells become metastatic through the EMT process. Transcription of a set of genes is altered in EMT, and the alterations correlate with metastatic potential. A drug that can block these gene expression changes may directly target metastasis. In addition, evidence suggests that EMT may allow tumor cells to become drug resistant. A quantitative high-throughput gene chip assay, ArrayPlate, will test extracts for their effect on the EMT gene expression signature. The extracts are derived from Sonoran desert plants and associated microorganisms recently isolated by the Southwest Center for Natural Product Research and Commercialization, at the University of Arizona. Phase II will follow up on reconfirmed hit fractions identified in Phase I. Fractions will be further separated and retested to attempt to isolate and identify active compounds. Compounds with sufficient activity will be tested in in vitro EMT models and in in vivo models of metastatic cancer. Novel therapeutics that target cancer EMT and so blocking metastasis may be useful in treating particular types of cancer especially in combination with other drug regimens, and may help reduce drug resistance. PUBLIC HEALTH RELEVANCE: Metastasis, the ability of cells to leave a tumor site and spread to other sites, is the major cause of death in cancer. Recent evidence suggests that there is one general mechanism of genetic reprogramming that is used by all tumors in becoming metastatic. The goal of this grant is to discover a new class of cancer drugs that will not stop the growth of tumor cells, but instead directly block metastasis, by interfering with this genetic reprogramming mechanism.